PROJECT SUMMARY/ABSTRACT An estimated 3.1 million cases of myocarditis/cardiomyopathy were diagnosed in 2017. Patients with myocarditis are at risk of sudden death from acute heart failure and the incidence and severity of myocarditis is higher in men than women. Exercise typically improves cardiac function; however, during viral myocarditis exercise can precipitate heart failure leading to current guidelines recommending that patients abstain from exercise for 3-6 months after diagnosis. Enteroviruses including coxsackievirus B3 (CVB3) are a common cause of myocarditis in the US. Although several studies published 30 years ago found that exercise increased viral replication and death in mice with viral myocarditis, no recent studies have examined the reason for heart failure following exercise. We recently published that in normal, healthy mice exercise induces mitochondrial fission through ?1 adrenergic receptor (AR) signaling resulting in fragmented mitochondria (i.e., smaller, more circular) with enhanced energy production compared to sedentary mice. Additionally, we found that CVB3 requires mitochondrial fission for viral replication. The overall goal of this proposal is to determine whether sex differences in ?1AR-induced mitochondrial fission with exercise in cardiomyocytes or mice with CVB3 myocarditis lead to increased viral replication, mitochondrial dysfunction, cardiomyocyte cell death, and bioenergetic failure resulting in heart failure.